What Is the Best Mechanical Ventilation Strategy in ARDS?

15

What Is the Best Mechanical Ventilation Strategy in ARDS? Andrew C. Steel, Joan R. Badia, Niall D. Ferguson

Acute respiratory distress syndrome (ARDS) is the catastrophic response of the lung to an injury that results in severe respiratory failure. It has been recognized as a clinical entity in adults for more than 40 years1 and affects more than 100,000 adults in the United States every year.2 Despite intensive management, outcomes remain poor. Reported mortality rates in observational studies persist at between 40% and 50%, and long-term morbidity affects most survivors.3,4

PATHOPHYSIOLOGY AND CLINICAL FEATURES OF ARDS The damage to the lungs in ARDS can occur after a direct insult to the lung (pulmonary ARDS) or due to indirect damage through the alveolar epithelium (extrapulmonary ARDS). Patients with ARDS generally share several constant characteristics that identify the condition. First, ARDS typically develops after exposure to at least one of a well-known list of risk factors (Table 15-1).5 Second, ARDS has an acute onset and is persistent over time. One of the most relevant clinical features is the presence of bilateral pulmonary airspace opacities in the chest radiograph. Severe impairment of gas exchange with hypoxemia and decrease of pulmonary compliance are also hallmarks of ARDS. The underlying cause of ARDS is extremely complex and to date is incompletely understood. It appears to involve the initiation of an inflammatory cascade within the alveolar-capillary endothelium or epithelium, and a wide range of inflammatory cells, cytokines, and chemokines have been implicated in this process. At least in its early stages, ARDS represents the pathologic state of diffuse alveolar damage (DAD).6–8 There is damage to both endothelial and epithelial layers6,8–11 of the alveolar-capillary membrane with resultant edema and alveolar flooding rich in proteins and hemorrhage, leading to hyaline membrane formation and fibrosis.6,10 These changes can overlap and evolve over hours to days and result in a loss of the barrier and gas exchange functions of the lung (Table 15-2).6,8,12–14 The clinical consequence is a severe heterogeneous injury to the lung that results in refractory hypoxemia and decreased lung compliance. Mechanical ventilation in this scenario is challenging because it is necessary to support respiratory function while minimizing further lung injury that may be associated with mechanical ventilation.

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The most widely used definition of ARDS is that proposed by the American-European Conference Committee (AECC), published in 1994 (Table 15-3).15 ARDS is defined by the acute onset of hypoxemia (with PaO2/FIO2 ratio < 200), the presence of bilateral infiltrates on chest radiography consistent with pulmonary edema, and pulmonary capillary occlusion pressure higher than 18 mm Hg or the clinical absence of left atrial hypertension. This definition has well-known limitations16; some of the criteria used in this definition are a matter of strong debate,17 and there is relatively poor correlation with tissue diagnosis of DAD.18

STRATEGIES FOR THE MANAGEMENT OF ARDS When Ashbaugh and colleagues first described ARDS in 1967,1 mechanical ventilation was already considered central to successful management. Evidence from clinical and experimental data has proved that ventilatory technique can contribute to lung injury and increased mortality. To date, there is no etiologic treatment available that can act on the pathogenic events that underlie the disease. Therefore, the focus of respiratory support by mechanical ventilation in patients with ARDS and acute lung injury (ALI) is to provide acceptable gas exchange while simultaneously minimizing further injury to the lung.

Conventional Ventilation Traditionally, most patients received mechanical ventilation using a standard approach of volume-controlled ventilation with tidal volumes ranging from 10 to 15 mL/kg. Notably, the use of positive end-expiratory pressure (PEEP) has varied throughout the years but has rarely exceeded 10 to 15 cm H2O. An end-inspiratory airway pressure of less than 50 cm H2O was considered acceptable in the absence of pneumothorax or surgical emphysema.19 The principal aim of this traditional strategy was to achieve normal physiologic indices as measured through arterial blood gas analysis. However, the original description of ARDS recognized the importance of PEEP and its association with lower mortality.1 Seven years later, Webb and Tierney published data demonstrating that high peak inflation pressures severely damaged the lung in rats, thus confirming the existence of ventilator-induced lung injury, and demonstrated

Chapter 15 What Is the Best Mechanical Ventilation Strategy in ARDS?

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Table 15-1 Risk Factors and Conditions Associated with ARDS Direct Lung Injury

Indirect Lung Injury

FREQUENT RISK FACTORS Pneumonia Aspiration of gastric contents

Sepsis Severe trauma with shock or prolonged hypotension Multiple transfusion

LESS FREQUENT RISK FACTORS Inhalational injury Pulmonary contusion Fat emboli Near drowning Reperfusion pulmonary edema*

Acute pancreatitis Cardiopulmonary bypass Severe burns Intravascular disseminated coagulopathy Cranial trauma Drug overdose

Figure 15-1. Computed tomography scan of an ARDS patient showing regional differences in lung parenchyma involvement.

*After pulmonary transplantation or pulmonary thromboendarterectomy.

Table 15-2 Pathologic Features of ARDS Exudative Phase

Proliferative Phase

Diffuse alveolar collapse

Resolution and healing or fibrosis

Intrapulmonary shunt

Destruction of capillary network

Low ventilation-perfusion ratios

Increased alveolar dead space

Decreased compliance

High ventilation-perfusion ratios

Hypoxemia

Hypercarbia

PEEP more effective in reversing hypoxemia

PEEP less effective, may worsen hypercarbia

PEEP, positive end-expiratory pressure.

Table 15-3 American-European Consensus Conference Definition of Acute Lung Injury and ARDS Oxygenation*

Front Chest Radiograph

PAWP{

Acute lung injury

PaO2/FIO2 ratio
300 mm Hg

Bilateral infiltrates


18 mm Hg

ARDS

PaO2/FIO2 ratio
200 mm Hg

Bilateral infiltrates


18 mm Hg

*Irrespective of positive end-expiratory pressure level. { No evidence of left auricle hypertension or heart failure. Acute onset is required. PAWP, pulmonary artery wedge pressure.

that PEEP could attenuate this damage.20 In the 1980s, the use of computed tomography (CT) in ARDS clearly showed that consolidation in lungs affected by ARDS was not as uniform as suggested by the plain radiograph. An example of this particular heterogeneous distribution of lung damage and consolidation is shown in Figure 15-1. There is an appreciable volume of preserved lung and alveolar spaces that could be particularly vulnerable to high inflation pressures and volume because it could be receiving most of the inflation volume. In the acutely injured lung, less than 50% of the lung may contribute to gas exchange. These observations led to the concept of the “baby lung” as a functional entity.21,22 The concept conveniently illustrates that healthy regions of lung parenchyma bear more stress and strain than the collapsed and consolidated regions, which are somewhat protected from overdistention. Repeated overdistention of this smaller preserved lung during tidal ventilation was causative in lung injury. Key developments in the field of ARDS ventilation are summarized in Table 15-4. All this cumulative knowledge led to a consensus for the development of a ventilation strategy for lung protection in early 1993.23 The consensus was important in providing recommendations for clinical practice, defined the state of the art of mechanical ventilation in 1993, and continued to stimulate clinical research conducted in the field over the next decade. Today, we would regard conventional ventilation for a patient with ARDS to consist of two essential principles, each of which will be discussed in more detail below: l Lung protection: ventilation with low tidal volume (VT) and low airway plateau pressure (Pplat; surrogate of alveolar pressure) employing “permissive hypercapnia” when necessary l Lung recruitment: using high PEEP to recruit collapsed alveolar units and avoid further injury to the lung associated with high alveolar volume swings (volutrauma). This general principle has been included under the concept of open lung ventilation. Application of extremely high PEEP for short periods of time has been proposed as a method to achieve further recruitment (recruitment maneuvers).

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Section II

ACUTE LUNG INJURY AND ARDS

Table 15-4 Key Research Landmarks in ARDS Study

Key Development

Ashbaugh et al, 19671

The “original description” of ARDS suggesting a common pathway of lung injury irrespective of the initial injury

Webb & Tierney, 197420

An animal study illustrating the relationship among inflation pressure, PEEP, lung histology, and gas exchange. Confirmed the existence of ventilator-induced lung injury

Dreyfuss et al, 198836

Illustrated that inflation volume in mechanical ventilation may cause greater damage than airway pressure

37

Hickling et al, 1990

Advocated adopting pressure-limited ventilation and permissive hypercapnia strategies in ARDS management

Bernard et al, 199414

American-European Consensus Conference on ARDS published the current definition of ARDS and acute lung injury.

Tremblay et al, 199738

Introduction of the concept of biotrauma: high tidal volume ventilation without PEEP releases proinflammatory cytokines from lung tissue.

Amato et al, 199826

Small RCT showing a decrease in mortality associated with low tidal volume ventilation and positive endexpiratory pressure.

NIH/ARDSNet, 200027

Large trial confirming reduced mortality in ARDS patients ventilated with low tidal volumes. It concluded the debate raised by earlier conflicting smaller trials.

Gattinoni et al, 200139

The use of computed tomography in ARDS patients showed the heterogenicity of the lung injury.

Lung-Protective Ventilation Mechanical ventilation with low tidal volumes, and the subsequent decrease in transpulmonary pressure, is associated with a decrease in mortality. Despite evidence from animal studies, early clinical research published in the late 1990s by Stewart,24 Brower,25 and Amato26 and their colleagues delivered conflicting results. The National Institutes of Health and Acute Respiratory Distress Syndrome Network (NIH/ARDSNet) trial, published in 2000, marshalled the resources necessary for a large randomized controlled trial (RCT) to end the equipoise. The results showed a 9% absolute reduction in mortality rate in patients ventilated VT of 6 mL/kg and Pplat of less than 30 cm H2O compared with VT of 12 mL/kg and Pplat of less than 50 cm H2O.27 Tidal volumes were based on the calculation of predicted body weight for each individual patient, calculated using the Devine formula for both male and female patients. Volumes were adjusted between 4 and 8 mL/kg to maintain the plateau pressure below 30 cm H2O, and hypercapnia could ensue, although a pH above 7.30 was targeted. In 2006, the Acute Respiratory Insufficiency: Espan˜a Study (ARIES) investigators compared the use of low tidal volume ventilation and high PEEP with standard ventilation in a population persistently meeting criteria for ARDS at 24 hours of mechanical ventilation.28 Tidal volume in the study group (5 to 8 mL/kg) and PEEP replicated those of an earlier trial by Amato,26 whereas the control group received lower levels of PEEP and more moderate tidal volumes (9 to 11 mL/kg of predicted body weight). This trial was stopped early after demonstrating both decreased intensive care unit (53.3% versus 32%) and hospital mortality (55.5% versus 34%).28 Current guidelines strongly underline the use of low tidal volume ventilation and low pressures with permissive hypercapnia as needed in the management of ARDS and ALI. Table 15-5 summarizes the features of key studies that provide a strong body of evidence in this regard. Limitation of airway pressure, specifically plateau pressure (pressure measured after the inspiratory pause

in volume-controlled cycles) is an integral part of a lungprotective ventilation strategy. Traditionally, high airway pressures were avoided because of the risk for gross barotrauma. Although this remains essentially true, there is also sufficient evidence of inflammatory lung damage associated with large volume changes in the alveoli. Current targets of this approach in mechanical ventilation for ARDS are low tidal volume (in the range of 4 to 8 mL/kg of predicted body weight) and an airway plateau pressure below 30 cm H2O when this can be achieved.

Lung Recruitment The rationale for the use of PEEP lies with the theoretical basis for loss of lung compliance in ARDS patients. Four mechanisms have been proposed to explain the beneficial effect of PEEP in the injured lung: (1) increased functional residual capacity, thereby increasing the size of the so-called baby lung and reducing risk for volutrauma; (2) redistribution of alveolar lung water; (3) improved ventilation-perfusion mismatching; and (4) alveolar recruitment. As stated previously, the use of PEEP is also postulated to be protective in preventing the cyclical collapse of alveoli with tidal ventilation, splinting open alveoli throughout the respiratory cycle, and avoiding atelectrauma. Although there is general agreement among experts that some amount of PEEP is beneficial, an assertion supported by observational data,29 exactly what level of PEEP should be used has remained a contentious issue for decades. In recent years, several RCTs have examined this issue explicitly. Studies by Amato and colleagues26 and Villar and coworkers28 used a significantly higher PEEP in their study groups than in their controls (13.2 versus 9.3 cm H2O, and 14.1 versus 9.0 cm H2O, respectively); however, it is unclear how much (if any) of the survival benefits seen in these trials was attributable to a higher level of PEEP versus the lower tidal volumes that were also employed. Three large RCTs have now been published

Chapter 15 What Is the Best Mechanical Ventilation Strategy in ARDS?

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Table 15-5 Overview of Study Design and Findings of Major Randomized Controlled Trials Involving Comparison of Mechanical Ventilation with Low versus High Tidal Volume in ARDS and Acute Lung Injury Study*

No. of Patients

Tidal Volume (mL/kg PBW)

PEEP (cm H2O)

Mortality (%)

P Value

Amato et al, 199826 Conventional Protective Stewart et al, 1998

24

12

8.7  0.4

72

29

<6

16.4  0.4

38

P < .001

40

Conventional

60

10.7  1.4

7.2  3.3

47

Protective

60

7.0  0.7

8.6  3.0

50

58

10.3  7.7

10.7  2.3

38

58

7.1  1.3

10.7  2.9

47

Conventional

26

10.2  0.1

—

46

Protective

26

7.3  0.1

—

50

Conventional

429

11.8  0.8

8.6  3.6

40

Protective

432

6.2  0.9

9.4  3.6

31

N.S.

Brochard et al, 199841 Conventional Protective

N.S.

42

Brower et al, 1999

N.S.

ARDS Network, 200027

P ¼ .007

*Conventional: study group receiving mechanical ventilation with higher tidal volume; protective: study group receiving mechanical ventilation with low tidal volume. N.S., differences not statistically significant; PBW, predicted body weight; PEEP, positive end-expiratory pressure.

in which the question of PEEP level for lung protection has been isolated, with all patients in both groups receiving low tidal volumes in the range of 6 mL/kg.30–32 In both the ALVEOLI trial30 and the Lung Open Ventilation Study (LOVS),31 PEEP was determined according to higher and lower PEEP-FIO2 tables, whereas the ExPress trial compared lower levels of PEEP (5 to 9 cm H2O) with higher levels set to achieve a plateau pressure of 28 cm H2O.32 In keeping with the original open-lung approach, the LOVS trial also employed recruitment maneuvers. The ALVEOLI and ExPress trials were stopped early because of perceived low likelihood of achieving nominal statistical significance (futility), and this likely contributed to the large baseline imbalance in age (5 years, favoring the low PEEP group) in the ALVEOLI trial. The three trials are summarized in Table 15-6. In addition to the mortality results displayed, the LOVS and ExPress trials also demonstrated important reductions in the use of rescue therapy for refractory hypoxemia. Furthermore, the number of ventilator-free days in the ExPress trial was higher in the higher PEEP group. Taken together, these results suggest a possible survival benefit to high-PEEP strategies, particularly among patients with the most severe forms of ARDS. Although there is strong evidence and agreement in favor of the use of moderate or high PEEP, the optimal level of PEEP to apply in ARDS patients and the most appropriate method to titrate PEEP have not been determined. Lung recruitment refers to the dynamic process of reopening collapsed alveoli through an intentional increase in transpulmonary pressure. This recruitment effect can be achieved through a variety of maneuvers that apply high

and sustained airway pressures for a short period of time (e.g., 40 cm H2O for 40 seconds). Such maneuvers appear to improve oxygenation at least in the short term in most patients; however, the optimal pressure, duration, and frequency of such maneuvers are not yet determined.33–35 It is important to note that adverse events such as transient hypotension, barotrauma, and dysrhythmia are well described, and evidence of or high risk for barotrauma or unilateral lung involvement can be considered also as possible contraindications to these recruitment maneuvers. To date, routine use of recruitment maneuvers in ARDS patients is not supported by the available evidence; however, they may be useful in certain individual patients, when performed by experienced clinicians. Other modes of ventilation, such as bilevel and airway pressure release ventilation (APRV), have been proposed as tools to achieve ongoing lung recruitment while still preserving the purported benefits of spontaneous breathing. Currently, however, insufficient data exist to make a recommendation about the advisability of their use; further study is also needed here.

ADJUNCTS TO VENTILATION IN ARDS Multiple interventions have been described and investigated during the past 40 years as adjuncts to conventional ventilatory management, including both ventilatory and nonventilatory adjuncts. The list is extensive and includes independent lung ventilation, maintaining spontaneous ventilation, high-frequency ventilation, continuous positioning therapy, prone position, extracorporeal membrane

Section II

98

ACUTE LUNG INJURY AND ARDS

Table 15-6 Randomized Trials of Open Lung Strategies (No Confounding Interventions) A. SUMMARY OF STUDY PATIENTS AND INTERVENTIONS Study

N

Patients

PEEP

Mode

RMs

Pplat

ALVEOLI30 Open lung

549

PaO2/FIO2 < 300 High (PEEP/FIO2 chart)

AC

No


30 cm H2O

Control

Low (PEEP/FIO2 chart)

AC

No


30 cm H2O

High (PEEP/FIO2 chart)

PC

Yes


40 cm H2O

Low (PEEP/FIO2 chart)

AC

No


30 cm H2O

Open lung

To keep Pplat 30 cm H2O

AC

No

28-32 cm H2O

Control

5-12 cm H2O

AC

No


32 cm H2O

31

LOVS

PaO2/FIO2 < 250

983

Open lung Control ExPress32

PaO2/FIO2 < 300

767

B. SUMMARY OF METHODOLOGIC FEATURES Study

Randomization

Baseline Differences

Similarity in Other Aspects of Care

Intentionto-Treat

Stopped Early

ALVEOLI

Central automated

Age, by 5.5 yr (lower control group)

VT 6 mL/kg PBW weaning

Yes

Yes

LOVS

Central automated

Age, by 2 yr (higher control group)

VT 6 mL/kg PBW weaning

Yes

No

ExPress

Central automated

None

VT 6 mL/kg PBW weaning

Yes

Yes

C. MORTALITY Study

Timing

Group Rates (%)

Unadjusted RR (95% CI)

Adjusted RR (95% CI)

Hospital

27.5

1.11

0.91

24.9

(0.84-1.46)

(0.69-1.20)

36.4

0.90

0.97

40.4

(0.77-1.05)

(0.84-1.12)

27.8

0.89

N/A

31.2

(0.72-111)

ALVEOLI Open lung Control LOVS Open lung

Hospital

Control ExPress Open lung Control

28 days

CI, confidence interval; RMs, recruitment maneuvers; RR, risk ratio; PBW, predicted body weight; Pplat, plateau pressure; VT, tidal volume.

oxygenation, inhaled NO, partial liquid ventilation, aerosolized prostacyclin, surfactant, and multiple anti-inflammatory drugs and antioxidants among others. Most of these are covered in other chapters in this book.

CONCLUSION Ventilatory strategies that minimize damage to the lung are essential to reducing the morbidity and mortality from

ARDS. There is strong evidence that the manner in which ARDS patients are ventilated has a great effect on their mortality. Limiting tidal volumes and inspiratory pressures is a fundamental tenet of lung protection, along with at least low-moderate levels of PEEP. Attempts to open the lung using higher levels of PEEP with or without recruitment maneuvers may be beneficial, but definitive data are lacking. The role of additional adjuncts such as high-frequency ventilation and prone positioning is still unproved and requires further evaluation.

Chapter 15 What Is the Best Mechanical Ventilation Strategy in ARDS?

AUTHORS’ RECOMMENDATIONS • Ventilator-associated lung injury is an important contributor to mortality in patients with ALI and ARDS. • Goals of ventilation in ARDS have evolved to achieving acceptable gas exchange while minimizing further injury to the lung. • Use of lower tidal volumes (4 to 8 mL/kg of predicted body weight) and targeting airway plateau pressure below 30 cm H2O should be considered key factors in lung-protective ventilation. • Although it appears that some PEEP should be used, just how much PEEP to apply to which patients remains controversial.

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